Pro- and Anti-Inflammatory Cytokines’ Implication in Right Heart Disease, Arrhythmogenesis, and Atrial Fibrillation

Figures

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  Figure 1. Proposed pathophysiological connections between RHD, specific inflammatory cytokines, structural and electrical remodeling, and the onset or maintenance of AF. It is suggested that RHD is accompanied by expression of markers of hypertrophy and dilation such as Acta1, Myl7, or Piezo1. Such remodeling might initiate RV and RA inflammation involving IL-1β, IL6, and TNF-α, which, if not attenuated, can stimulate the production and maintenance of COL1A1, COL3A1, or α-SMA. Persistent and irreversible RA fibrosis deposits can be responsible for formation of low-voltage zones, perturbed conduction and arrhythmogenesis, and AF. Abbreviations: α-SMA, alpha smooth-muscle actin; Acta1, alpha actin 1; COL, collagen; IL, interleukin; Myl7, myosin light chain 7; Piezo1, piezo-type mechanosensitive ion channel component 1; TNF-α, tumor necrosis factor alpha.

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  Figure 2. Potential inflammation- and oxidative stress-induced arrhythmogenic cellular remodeling as suggested by animal models of RHD. The progressive RA and RV myocardial remodeling observed in RHD might be associated with activation of biomarkers of oxidative stress and inflammation involved in arrhythmogenic pathophysiological changes affecting cardiac cells [15,25,28,29]. Established mechanisms in human pathophysiology are identified by a green star. Emerging/speculative pathways based on recent preclinical evidence are identified by a yellow star. Abbreviations: CM, cardiomyocyte; EC, endothelial cell; FB, fibroblast; IL, interleukin; RA, right atrium; RHD, right heart disease; ROS, reactive oxidative species; RV, right ventricle.

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  Figure 3. Emerging paradigm of inflammation-associated electrical remodeling with potential relevance in RHD. Progressive myocardial remodeling in RHD might provoke a local inflammatory response affecting the cardiomyocytes, leading to arrhythmogenesis and AF. Established mechanisms in human pathophysiology are identified by a green star. Emerging/speculative pathways based on recent preclinical evidence are identified by a yellow star. Abbreviations: Ca2+, calcium; CM, cardiomyocyte; Ito, transient outward K+ channel; RHD, right heart disease; RyR, ryanodine 2 receptor; SR, sarcoplasmic reticulum.

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  Figure 4. Suggested beneficial impact of RvD1-induced inflammation resolution in a rat model of RHD and AF. In a rat model of monocrotaline-induced right heart disease (RHD), resolvin-D1 (RvD1) has been demonstrated to prevent atrial inflammation and fibrosis, but not myocardial hypertrophy. Interestingly, RvD1’s effects on inflammation and fibrosis were accompanied with attenuation of AF vulnerability in RHD. Established mechanisms in human pathophysiology are identified by a green star. Emerging/speculative pathways based on preclinical evidence are identified by a yellow star. Question mark with blue circle indicates a preventive effect of RvD1 which requires further demonstration.

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  Figure 5. Potential beneficial impact of anti-inflammatory cytokines in RHD to prevent arrhythmogenesis. Mounting evidence suggests that anti-inflammatory cytokines such as interleukin-(IL)-10, IL13, or IL37 might promote cardio-protection by promoting T cell-impaired efferocytosis and M2 macrophage recruitment in injured tissue. In addition, anti-inflammatory cytokines may activate the secretion of further anti-inflammatory cytokines while decreasing pro-inflammatory signals. Such an anti-inflammatory response might contribute to reducing fibrosis and preserving the myocardial function and structure. Altogether, anti-inflammatory signaling has the potential to prevent the development of the arrhythmogenic substrate, which reduces the vulnerability for cardiac arrhythmias. Established mechanisms in human pathophysiology are identified by a green star. Emerging/speculative pathways based on recent preclinical and clinical evidence are identified by a yellow star.